1,2,3 Oxadiazolium salts

ABSTRACT

The disclosed [[2-(substituted amino)-2-phenylethyl]-nitrosoamino]acetonitrile derivatives and the ring closed oxadiazolium salts thereof as well as their pharmaceutically acceptable acid addition salts are antihypertensive agents useful in the treatment of hypertension.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.193,043, filed Oct. 2, 1980 by Reinhardt P. Stein now U.S. Pat. No.4,289,885.

BACKGROUND OF THE INVENTION

It has been suggested by Kikuchi et al. Jap. J. Pharmac. 20 23-43 (1970)that sydnonimines containing an amine in 3-position produce hypotensionwhile sydnonimines containing an alkyl, cycloalkyl or dialkylaminoalkylgroup in 3-position produce hypertension.

DESCRIPTION OF THE INVENTION

In accordance with this invention there is provided a group of5-amino-3-[2-substituted amino)-2-phenylethyl]-1,2,3-oxadiazolium saltsand [[2-(substituted amino)-2-phenylethyl]nitrosoamino]acetonitrilederivatives which are antihypertensive agents useful in the treatment ofhypertension.

The oxadiazolium salts of this invention are also useful asintermediates in the production of3-[2-(dimethylamino)-2-phenylethyl]-N-[(phenylamino)carbonyl]sydnoneimine derivatives disclosed and claimed in copending application Ser.No. 193,043, filed Oct. 2, 1980 now U.S. Pat. No. 4,289,885.

The oxadiazolium salts of this invention are represented by thefollowing structural formula: ##STR1## in which R¹ and R² are,independently, hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6carbon atoms, halo, perfluoroalkyl of 1 to 3 carbon atoms, nitro,alkanoyl of 2 to 4 carbon atoms, or alkoxycarbonyl of 2 to 4 carbonatoms;

R⁵ and R⁶ are, independently, hydrogen or methyl;

R⁷ and R⁸ are, independently, alkyl of 1 to 4 carbon atoms, or whentaken with the nitrogen atom to which they are attached, form apiperidinyl, pyrolidinyl, morpholinyl, N-alkyl piperazinyl in which thealkyl group contains from 1 to 6 carbon atoms or N-phenylpiperazinylgroup; and

X is the anion of a strong acid having a pKa below 2.

The oxadiazolium salts of this invention revert to the correspondingnitroso-nitrile precursor via a pH dependent ring opening. Ring openingoccurs rapidly under basic conditions and slower in mild acid, inessence demonstrating the reverse of the ring closing accomplished withstrong acids. The nitroso-nitriles are, both intermediates for theantihypertensive oxadiazolium salts and active antihypertensive agentsin their own right.

Thus, in accordance with this invention there is also provided a groupof nitroso-nitriles useful as antihypertensive agents and in theproduction of oxadiazolium antihypertensive salts, of the formula:##STR2## in which R¹ and R² are, independently, hydrogen, alkyl of 1 to6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halo, perfluoroalkyl of 1to 3 carbon atoms, nitro, alkanoyl of 2 to 4 carbon atoms, oralkoxycarbonyl of 2 to 4 carbon atoms;

R⁵ and R⁶ are, independently, hydrogen or methyl;

R⁷ and R⁸ are, independently, alkyl of 1 to 4 carbon atoms, or whentaken with the nitrogen atom to which they are attached, form apiperidinyl, pyrolidinyl, morpholinyl, N-alkyl piperazinyl in which thealkyl group contains from 1 to 6 carbon atoms or N-phenylpiperazinylgroup;

or a pharmaceutically acceptable salt thereof.

In the preceding structural formulae, it is generally preferred that thehalo substituent be chlorine, bromine or fluorine although iodine isacceptable. Likewise, it is preferred that the alkyl and alkoxysubstituents be relatively small, the methyl, ethyl, propyl, isopropyl,methoxy, ethoxy, propoxy and isopropoxy groups being preferred.

The pharmaceutically acceptable acid addition salts of the compounds ofthis invention are conventionally produced by the method and from any ofthe acids disclosed in U.S. Pat. No. 3,277,108, which exhibit a pKabelow 2. The salt is preferably that formed during cyclization of thenitrosonitrile, such as with hydrochloric, hydrobromic, sulfuric,phosphoric, methane sulfonic, p-toluene sulfonic acid, and the like. Theanion can be replaced with a desired anion by ion exchangechromatography following conventional procedures. The salts formed withthe aminic bases of this invention are generally water soluble,dissociating sufficiently to dissolve in aqueous medium to provide ahomogeneous solution. Thus, the compounds of this invention may beformulated for administration in aqueous vehicle for practical dosing toreduce blood pressure in patients unable to receive treatment orally.

The compounds of this invention contain one chiral center when R⁵ ishydrogen and two chiral centers when R⁵ is methyl. Thus, depending uponthe identity of the substituent R⁵, there is obtained either one or tworacemic mixtures of product. The epimers and optical isomers are readilyseparable by standard techniques well known to the chemist. By selectionof the desired starting material, the product can be limited to a singleracemic mixture of isomers.

The oxadiazolium salts and the nitroso-nitriles of this invention areprepared by conventional techniques employed in the preparation ofsydnonimines.

The starting materials are either known or preparable by routinesynthetic methods. Thus, a properly substituted 2-tertiaryamino-2-phenylethyl amine is cyanomethylated with a reactant XCH₂ CNwhere X may be --OH, --Br, --Cl, tosyl, and the like to form theintermediate ##STR3## which is nitrosated with an excess of NaNO₂ inaqueous HCl to yield the nitroso-nitrile ##STR4## which is then reactedwith excess strong acid to form the oxadiazolium salt.

The following example illustrates the preparation ofd,l-[[2-(dimethylamino)-2-phenylethyl]nitrosoamino]acetonitrile and itsuse as an intermediate in the production ofd,l-5-amino-3-[2-(dimethylamino)-2-phenylethyl]-1,2,3-oxadiazoliumchloride.

EXAMPLEdl-5-Amino-3-[2-(dimethylamino)-2-phenylethyl]-1,2,3-oxadiazoliumchloride

Dissolve dl-2-dimethylamino-2-phenylethylamine, dihydrochloride (4.74g.) in water (50 ml.), stir and cool with an ice-bath. Add 37% aqueousformaldehyde solution (2.0 ml.), stir for 10 minutes, then drip in asolution of potassium cyanide (1.30 g.) in water (20 ml.). Stir the coldsolution for 1 hour, then cool further to 0° C. (ice-salt bath). Drip ina solution of sodium nitrite (1.4 g.) in water (15 ml.) followed by 5Naqueous HCl (8 ml.). Stir, then again drip in a solution of sodiumnitrite (1.4 g.) in water (15 ml.) and continue stirring for 3 hours,allowing the reaction to warm to room temperature. Drip in 5N aqueoussodium hydroxide solution unitl a pH of 10 is attained. Quickly extractwith diethyl ether, then dry and evaporate the solvent in vacuo. Pumpdry, then treat the oil in diethyl ether with decolorizing carbon,filter and evaporate, then pump to obtaindl-[[2-(dimethylamino)-2-phenylethyl] nitrosoamino]acetonitrile as anoil (about 3 g.). To characterize this product dissolve a sample (313mg.) in methylene chloride, treat with 5N isopropanolic-HCl (1 ml.),then evaporate the solvent in vacuo. Crystallize the residue fromacetone, filter to obtain the hydrochloride salt (210 mg.); m.p.164°-166° C.

Analysis for: C₁₂ H₁₆ N₄ O.HCl. Calculated: C, 53.63; H, 6.38; N,20.85%. Found: C, 53.51; H, 6.34; N, 21.31%.

Dissolve [[2-(dimethylamino)-2-phenylethyl]nitrosoamino]-acetonitrile(4.43 g.) in methylene chloride, add excess 5N isopropanolic--HCl (8ml.) and let stand overnight. Filter to obtain 1.86 g. of the crudetitle product, m.p. 150° C. (dec).

Combine the product of several runs (3.34 g.), dissolve in 70% aqueousethanol, treat with decolorizing carbon, filter and dilute the filtratewith isopropanol. Evaporate the solvents in vacuo, cover the remainingglassy material with methylene chloride and let stand to crystallize.Filter to obtain 2.62 g. of the title product as the hydrochloridehydrate, m.p. 157°-158° C. (dec).

Analysis for: C₁₂ H₁₇ ClN₄ O.HCl 1.5H₂ O. Calculated: C, 43.38; H, 6.37;N, 16.86%. Found: C, 43.66; H, 5.85; N, 17.49%.

The antihypertensive activity ofd,l-5-amino-3-(2-(dimethylamino)-2-phenylethyl)-1,2,3-oxadiazoliumchloride, hydrochloride, which compound is representative in itsactivity of the other compounds of this invention, was established byorally administering the compound to a group of unanesthetized,spontaneously hypertensive rats while indirectly measuring theirsystolic blood pressure employing a Decker Caudal Plethysmograph. Adecrease of 51 mmHg blood pressure was found at 1.5 hours after oraladministration of 50 mg/kg of compound and a decrease of 40 mmHg at 1.5and 4 hours at 25 mg/kg was demonstrated.

Thus, the antihypertensive agents of this invention are useful intreatment of hypertension and as such they may be administered to apatient suffering from hypertension, orally or parenterally, in anamount of from about 25 to 50 mg/kg or more, based upon the testresults, in single or divided doses. The dosage regimen and route ofadministration may be varied by the attending physician to achieve thedesired response depending upon the condition of the patient relative toage, severity of hypertensive state, etc.

What is claimed is:
 1. A compound of the formula: ##STR5## in which R¹and R² are, independently, hydrogen, alkyl of 1 to 6 carbon atoms,alkoxy of 1 to 6 carbon atoms, halo, perfluoroalkyl of 1 to 3 carbonatoms, nitro, alkanoyl of 2 to 4 carbon atoms, or alkoxycarbonyl of 2 to4 carbon atoms;R⁵ and R⁶ are, independently, hydrogen or methyl; R⁷ andR⁸ are, independently, alkyl of 1 to 4 carbon atoms, or when taken withthe nitrogen atom to which they are attached, form a piperidinyl,pyrolidinyl, morpholinyl, N-alkyl piperazinyl in which the alkyl groupcontains from 1 to 6 carbon atoms or N-phenylpiperazinyl group; and X isthe anion of a strong acid having a pKa below 2; or a pharmaceuticallyacceptable acid addition salt thereof.
 2. A compound of claim 1 of theformula: ##STR6## in which R¹ and R² are, independently, hydrogen, alkylof 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, chloro, bromo,fluoro, perfluoroalkyl of 1 to 3 carbon atoms, nitro, alkanoyl of 2 to 4carbon atoms or alkoxycarbonyl of 2 to 4 carbon atoms;R⁵ and R⁶ are,independently, hydrogen or methyl; R⁷ and R⁸ are, independently, alkylof 1 to 3 carbon atoms or when taken with the nitrogen atom to whichthey are attached, form a piperidinyl, pyrolidinyl, morpholinyl,N-alkylpiperazinyl in which the alkyl group contains from 1 to 3 carbonatoms on N-phenylpiperazinyl group; and X is an anion of a strong acidhaving a pKa below 2; or a pharmaceutically acceptable acid additionsalt thereof.
 3. A compound of claim 1 which is5-amino-3-[2-(dimethylamino)-2-phenylethyl]-1,2,3-oxadiazolium chlorideor a pharmaceutically acceptable acid addition salt thereof.